CN109912531B

CN109912531B - Preparation method of high-purity febuxostat

Info

Publication number: CN109912531B
Application number: CN201910264559.8A
Authority: CN
Inventors: 张庆华; 陈波; 阎智勇
Original assignee: Jiangsu Fangsheng Pharmaceutical Co ltd
Current assignee: Jiangsu Fangsheng Pharmaceutical Co ltd
Priority date: 2019-04-03
Filing date: 2019-04-03
Publication date: 2023-03-10
Anticipated expiration: 2039-04-03
Also published as: CN109912531A

Abstract

The invention relates to a preparation method of febuxostat, wherein after 2- (3-formyl-4-hydroxyphenyl) -4-methylthiazole-5-carboxylic acid ethyl ester and isobutyl bromide react, the reaction solution is subjected to the following post-treatment: 1) Adding purified water to separate out primary crystals; 2) Pulping the primary crystals with purified water to obtain secondary crystals; 3) The secondary crystals were recrystallized from an ethanol-formic acid solution at a mass ratio of 1.2 to 2.0 to obtain compound (2- (3-formyl-4-isobutoxy-phenyl) -4-methyl-thiazole-5-carboxylic acid ethyl ester (FBT-1). By optimizing the post-treatment of the reaction, the purity and yield of the key intermediate are obviously improved, so that the purity and yield of the final product febuxostat are improved.

Description

Preparation method of high-purity febuxostat

Technical Field

The invention relates to the field of synthesis of small molecular compounds, in particular to a method for synthesizing a drug and an intermediate thereof.

Background

Febuxostat, the chemical name is 2- (3-cyano-4-isobutoxy-phenyl) -4-methyl-thiazole-5-formic acid, and the chemical structural formula is as follows:

febuxostat is a non-purine xanthine oxidase selective inhibitor and is used for treating hyperuricemia of gout patients. Febuxostat can inhibit the activity of xanthine oxidase to prevent and reduce the synthesis of uric acid by hypoxanthine or xanthine, thereby achieving the purpose of reducing blood uric acid. Compared with other purine drugs for treating gout, febuxostat has the advantages that: firstly, the xanthine oxidase emesia inhibiting effect is obvious, and the effect of reducing uric acid is stronger and more durable; secondly, the enzyme activity in purine and pyridine metabolism is not influenced, and the safety is high.

The prior art discloses an advantageous synthetic route, as follows:

compared with other routes, the synthetic route has high reaction conversion rate in each step and relatively simple post-treatment, and is the mainstream choice at present. In the route, the purity of the intermediate FBT-1 (2- (3-formyl-4-isobutoxy-phenyl) -4-methyl-thiazole-5-ethyl formate) has great influence on the total yield and purity of the target drug FBT-1. The conversion rate of the last two steps is high, the byproducts are few, relatively speaking, the conversion rate of the first step reaction is low, the reaction product contains a certain amount of raw material FBT-SM1, and the raw material is difficult to be completely separated from FBT-1 in the post-treatment process, so that the next step reaction is carried out, and the purity of the target medicament is influenced finally. In order to try to remove impurities, a portion of the intermediate is also left in the mother liquor, and the yield is therefore severely affected.

CN103058950A adopts the synthetic route to obtain the intermediate (compound II), and the intermediate is refined by DMF, and the yield of the obtained refined product is only 57%; the febuxostat prepared in the subsequent step needs to be refined by ethanol, the yield is 84.0%, and the hazardous waste generated by refining is large. In the preparation method of this intermediate disclosed in CN104529935, the crude product is washed once with DMF, twice with water, and finally twice with methanol; the method has complicated refining steps, produces a large amount of waste liquid industrially, increases the environmental protection cost, and has lower yield of the obtained refined product; in CN101665471, the obtained intermediate is not subjected to a refining step, and has low purity and low yield; the febuxostat prepared subsequently needs to be refined by ethanol, the yield is only 70%, and the hazardous waste generated by refining is large.

Therefore, the prior art needs to further optimize the preparation method of febuxostat intermediate FBT-1 so as to improve the total yield and purity of febuxostat.

Disclosure of Invention

The invention aims to provide a preparation method of febuxostat, which is used for improving the purity and yield of a product.

According to the invention, the preparation method of febuxostat comprises the following steps (see the background art section in a scheme):

1) And (3) substitution reaction: reacting a compound of formula FBT-SM1 with isobutyl bromide to obtain a compound of formula FBT-1;

2) Cyaniding reaction: reacting a compound of formula FBT-1 with hydroxylamine hydrochloride to obtain FBT-2;

3) Hydrolysis reaction to hydrolyze FBT-2 to obtain febuxostat,

wherein, after the substitution reaction is finished, the reaction solution is post-treated as follows:

a) Adding purified water to separate out primary crystals;

b) Pulping the primary crystal with purified water to obtain a secondary crystal;

c) And recrystallizing the secondary crystal with an ethanol-formic acid solution with the mass ratio of 1.2-2.0 to obtain the compound FBT-1.

Preferably, the molar ratio of the compound FBT-SM1 to isobutyl bromide (FBT-SM 2) is in the range of 1. More preferably 1.

Preferably, the pH is adjusted to not more than 8, preferably 6.5 to 8, during the beating process.

Preferably, the mass ratio of the ethanol-formic acid solution is 1.4-1.5.

Preferably, the ethanol-formic acid solvent is used in an amount of 8 to 12 times, preferably 9 to 10 times, the mass of the secondary crystals.

The invention optimizes the synthesis link of the intermediate 2- (3-formyl-4-isobutoxy-phenyl) -4-methyl-thiazole-5-ethyl formate of febuxostat, and obviously improves the purity and yield of the intermediate, thereby improving the purity and yield of the final product febuxostat.

Detailed Description

The invention adopts the synthesis route, and optimizes the post-treatment of the reaction system after the first step of reaction (substitution) is finished.

In the substitution reaction of the invention, the ratio of raw materials FBT-SM1 and isobutyl bromide (FBT-SM 2) is preferably controlled in the range of 1. The reaction is preferably carried out at a temperature of 75 to 85 ℃ and for a reaction time of 5 to 8 hours, preferably 6 to 7 hours. After the reaction is finished, cooling the system to 20-30 ℃. Adding purified water, and performing heat preservation and crystallization. The crude product is then slurried with purified water and the pH is controlled to be no greater than 8, preferably between 5 and 8, more preferably between 6 and 8, and most preferably between 6.5 and 8. In this pH range, inorganic salt impurities such as potassium bicarbonate, potassium bromide, etc. in the crude product have been substantially removed. The pulping process can be completed within 10-20 minutes, and secondary crystals are obtained after filtration and drying.

In the present invention, the aforementioned secondary crystal is recrystallized using a composite solvent composed of ethanol and formic acid in a mass ratio of 1. The amount of the complex solvent to be used is 8 to 12 times (by mass) the amount of the crude product, preferably 9 to 10 times. By adopting the composite solvent with the numerical range for recrystallization, excellent yield and purity can be obtained, and the febuxostat target product can be obtained with high yield and high purity.

EXAMPLE 1 preparation of FBT-1

A500 ml round-bottomed flask was charged with 129g of DMF, 17g (0.058 mol) of ethyl 2- (3-formyl-4-hydroxyphenyl) -4-methylthiazole-5-carboxylate, 32.24g (0.233) of potassium carbonate and 0.2g of potassium iodide. A further 20g (0.146) of isobutylbromide (FBT-SM 2) was added. After the addition, the temperature is raised to 75 to 85 ℃ and the reaction is carried out for 6 hours. After the reaction is finished, cooling to 20-30 ℃. And 136g of purified water is added into the reaction kettle, and the temperature is kept between 20 and 30 ℃ for crystallization for 1 hour. After the heat preservation, the mixture was filtered, the obtained filter cake was beaten with purified water, the pH of the beaten solution was measured to be 7, and the filtered mixture was dried to obtain 19.4g of a crude product of ethyl 2- (3-formyl-4-isobutoxy-phenyl) -4-methyl-thiazole-5-carboxylate (FBT-1).

67g of ethanol, 102g of formic acid and 19.4g of crude 2- (3-formyl-4-isobutoxy-phenyl) -4-methyl-thiazole-5-ethyl formate (FBT-1) are added into a 500ml round-bottomed bottle, the mixture is stirred and heated to 60-70 ℃, the temperature is reduced to 15-30 ℃ after the mixture is dissolved and cleaned for crystallization for 1 hour, after the crystallization is finished, the mixture is filtered and dried to obtain 18.4g of refined 2- (3-formyl-4-isobutoxy-phenyl) -4-methyl-thiazole-5-ethyl formate (FBT-1), the refining rate is 94.8 percent, the total yield is 90.8 percent, the content of the intermediate is 99.80 percent, and the maximum single impurity is 0.07 percent.

EXAMPLE 2 preparation of FBT-1

A500 ml round-bottomed flask was charged with 129g of DMF, 17g (0.058 mol) of ethyl 2- (3-formyl-4-hydroxyphenyl) -4-methylthiazole-5-carboxylate, 32.24g (0.233) of potassium carbonate and 0.2g of potassium iodide. A further 20g (0.146) of isobutylbromide (FBT-SM 2) was added. After the addition, the temperature is raised to 75 to 85 ℃ and the reaction is carried out for 6 hours. After the reaction is finished, cooling to 20-30 ℃. And 136g of purified water is added into the reaction kettle, and the temperature is kept between 20 and 30 ℃ for crystallization for 1 hour. After the heat preservation, the mixture is filtered to obtain a filter cake, the filter cake is pulped by purified water, the pH value of the pulping liquid is 10, and the obtained product is dried after filtration to obtain 21.5g of a crude product of 2- (3-formyl-4-isobutoxy-phenyl) -4-methyl-thiazole-5-ethyl formate (FBT-1).

67g of ethanol, 102g of formic acid and 21.5g of crude 2- (3-formyl-4-isobutoxy-phenyl) -4-methyl-thiazole-5-ethyl formate (FBT-1) are added into a 500ml round-bottomed bottle, the mixture is stirred and heated to 60-70 ℃, the temperature is reduced to 15-30 ℃ after the mixture is dissolved and cleaned for crystallization for 1 hour, after the crystallization is finished, the mixture is filtered and dried to obtain 19.2g of refined 2- (3-formyl-4-isobutoxy-phenyl) -4-methyl-thiazole-5-ethyl formate (FBT-1), the refining rate is 89.3%, the total yield is 94.7%, the content of the intermediate is 98.40%, and the maximum single impurity is less than 0.10%.

This example does not adjust the PH during the pulping process and the results show that although the overall yield of the product is improved, the purity of the intermediate obtained is somewhat reduced.

EXAMPLE 3 preparation of FBT-1

A500 ml round-bottomed flask was charged with 129g of DMF, 17g (0.058 mol) of ethyl 2- (3-carboxaldehyde-4-hydroxyphenyl) -4-methylthiazole-5-carboxylate, 32.24g (0.233) of potassium carbonate and 0.2g of potassium iodide. A further 20g (0.146) of isobutylbromide (FBT-SM 2) was added. After the addition, the temperature is raised to 75 to 85 ℃ and the reaction is carried out for 6 hours. After the reaction is finished, cooling to 20-30 ℃. And 136g of purified water is added into the reaction kettle, and the temperature is kept between 20 and 30 ℃ for crystallization for 1 hour. After the heat preservation, filtering is carried out, a filter cake is obtained and is pulped by purified water, the pH value of pulping liquid is 10, and 21.5g of crude product of 2- (3-formyl-4-isobutoxy-phenyl) -4-methyl-thiazole-5-ethyl formate (FBT-1) is obtained after filtering and drying.

67g of ethanol, 67g of formic acid and 19.4g of crude 2- (3-formyl-4-isobutoxy-phenyl) -4-methyl-thiazole-5-ethyl formate (FBT-1) are added into a 500ml round-bottomed bottle, the mixture is stirred and heated to 60-70 ℃, the temperature is reduced to 15-30 ℃ after the mixture is dissolved and cleaned for crystallization for 1 hour, after the crystallization is finished, 17.1g of refined 2- (3-formyl-4-isobutoxy-phenyl) -4-methyl-thiazole-5-ethyl formate (FBT-1) is obtained by filtering and drying, the refining is 88.1%, the total yield is 86.7%, the content of the intermediate is 98.72%, and the maximum single impurity is 0.09%.

The difference between this example and example 1 is that the recrystallization solvent is ethanol-formic acid solution with mass ratio of 1.

EXAMPLE 4 preparation of FBT-2

172.8g of formic acid, 16.0g of 2- (3-formyl-4-isobutoxy-phenyl) -4-methyl-thiazole-5-ethyl formate (FBT-1) prepared in example 1, 4.2g of hydroxylamine hydrochloride and 4.1g of sodium formate are added into a 500ml round-bottomed bottle, the mixture is stirred and heated to 105-110 ℃, the temperature is kept for 2 hours of heat preservation reaction, the reaction is finished, the temperature is reduced to 20-30 ℃, the mixture is kept for crystallization for 1 hour, the mixture is filtered, a filter cake is rinsed by 25.3g of ethanol, the mixture is filtered and dried to obtain 14.2g of 2- (3-cyano-4-isobutoxy-phenyl) -4-methyl-thiazole-5-ethyl formate (FBT-2), and the yield is 89.5%.

Example 5 preparation of FBT

Adding 114.0g of absolute ethyl alcohol, 6.0g of purified water and 1.6g of sodium hydroxide into a 500ml round-bottomed bottle, stirring for 0.5h to dissolve, adding 12.0g of the ethyl 2- (3-cyano-4-isobutoxy-phenyl) -4-methyl-thiazole-5-carboxylate (FBT-2) prepared in example 4, heating to 65-75 ℃, keeping the temperature for reaction for 5h, cooling to 20-30 ℃ after the reaction is finished, dropwise adding 5.0g of concentrated hydrochloric acid, adjusting the pH to 2-3, keeping the temperature for 2-30 ℃ to crystallize for 2h, filtering and drying to obtain 9.7g of a finished product of the 2- (3-cyano-4-isobutoxy-phenyl) -4-methyl-thiazole-5-carboxylic acid (FBT), wherein the yield is 88.0%, the febuxostat content is 99.86%, the maximum single impurity is 0.05%, and the finished product quality requirements in the pharmaceutical product declaration standard are met without additional refining.

The technical scheme of the invention is elaborated by combining the embodiment, and the invention obviously improves the purity and yield of the intermediate by optimizing the FBT-1 intermediate synthesis link, thereby improving the purity and yield of the final product febuxostat.

Claims

1. A preparation method of febuxostat is prepared by the following synthetic route:

1) And (3) substitution reaction: reacting a compound of formula FBT-SM1 with isobutyl bromide in a molar ratio of 1 to 2 to 3 to give a compound of formula FBT-1,

2) Cyanidation reaction: reacting a compound of formula FBT-1 with hydroxylamine hydrochloride to obtain FBT-2;

3) Hydrolysis reaction to hydrolyze FBT-2 to obtain febuxostat,

the method is characterized in that after the substitution reaction is finished, the reaction solution is subjected to the following post-treatment:

a) Adding purified water to separate out primary crystals;

b) Pulping the primary crystals with purified water to obtain secondary crystals;

2. The process according to claim 1, wherein the compound FBT-SM1 is present in a molar ratio to isobutylbromide of 1.

3. The method according to claim 1, wherein the pH is adjusted to not higher than 8 during the beating.

4. The method according to claim 1, wherein the pH is adjusted to 6.5 to 8 during the beating.

5. The production method according to claim 1, wherein the mass ratio of the ethanol-formic acid solution is 1.4 to 1.5.

6. The method according to claim 5, wherein the ethanol-formic acid solvent is used in an amount 8 to 12 times the mass of the secondary crystals.

7. The method according to claim 6, wherein the ethanol-formic acid solvent is used in an amount of 9 to 10 times the mass of the secondary crystals.